4-Boronophenylalanine (BPA) currently has Investigational New Drug (IND) status in the U.S.A. and is being extensively investigated in the U.S. and abroad for boron neutron capture therapy (BNCT) treatment of metastatic melanomas and other tumors. Its use to cure melanomas in Japan was reported in 1989. The rationale for its use is that BPA can be a mock biosynthetic precursor for melanin, which is normally made by the enzyme tyrosinase from dopa and tyrosine. It is widely believed that the pure enantiomer L-BPA, possessing S configuration, is more biologically active than is the D,L racemate.
The traditional synthetic route to D,L-BPA was developed by Snyder et al. in 1958 and reported in Journal Am Chem. Soc., 1958, 80, 835. Pure L-BPA has been prepared by Kemp et al. in 1980 by resolving the racemic product of Snyder's synthesis. Thus, D,L-BPA was esterified and enantioselectively hydrolysed using the enzyme .alpha.-chymotrypsin. More recently, Glass et al. in 1983 have reported the selective hydrolysis of the N-acetamide derivative, Glass, J.; Proc. First Intl. Symp. on Neutron Capture Therapy, Cambridge, Mass. 1983. All methods of resolution suffer from the inherent disadvantage that, at most, only 50% of the racemic material can be recovered as a pure enantiomer; for BNCT purposes, at least 50% of the .sup.10 B isotope is discarded during resolution.
Accordingly, an object of the invention is the development of a direct enantioselective synthesis of L-BPA utilizing an asymmetric hydrogenation of prochiral olefins using chiral 1,2-diphosphine complexes of rhodium, such as those summarized in, Asymmetric Synthesis, Morrison, L. D., Ed.; Vol. 5; Academic Press: New York, 1985, the disclosure of which is herein incorporated. This technique was originally developed at Monsanto Corporation for the manufacture of L-DOPA, see U.S. Pat. Nos. 4,005,127, 4,142,992, 4,220,590 and others.
The catalysts used in this invention are chelate complexes of rhodium (I) with chiral bisphosphines. There are two general types of chiral bisphosphines known, shown in the diagram below. Both types possess phosphine groups linked by a two-carbon chain. In type 1, the center(s) of chirality, responsible for asymmetric induction in the catalytic hydrogenation reactions, lies in this two-carbon chain by virtue of its unsymmetrical substitution i.e. R.sub.1 and/or R.sub.2 .noteq.H. Type 1 bisphosphines are usually derived and prepared from naturally occurring optically active biochemicals, are commercially available and inexpensive. Type 1 includes the compounds trivially named Prophos, Chiraphos, Norphos, Diop and Binap. Type 2 bisphosphines possess an unsubstituted ethylene group linking two chiral phosphine groups, i.e. R.sub.3 .noteq.R.sub.4. Type 2 ligands were developed at Monsanto Corp. (U.S. Pat. No. 4,220,590) and are prepared synthetically and chemically resolved into enantiomers. The optimal bisphosphine of this type is trivially named Dipamp. In the present invention type 1 ligands are preferred due solely to their availability but type 2 bisphosphines are also effective. ##STR1##
The active rhodium (I) catalyst is a cation which may be prepared in two ways. The first method is in-situ catalyst generation by combining appropriate amounts of bisphosphine and a suitable precursor rhodium complex such as [(diene)RhCl].sub.2, [(diene)Rh(acac)] (where diene may be 1,5-cyclooctadiene, norbornadiene or others and acac is acetonylacetone) or a cationic rhodium complex such as [(diene).sub.2 Rh]X may be used (where X is a non-coordinating anion). These components are combined in a organic medium and the hydrogenation substrate is subsequently added, then hydrogen. The second method is prior isolation of the catalyst complex, [(bisphosphine) (diene)Rh]X, as described herein; combination of the substrate with this catalyst and addition of hydrogen allows hydrogenation to proceed, the substrate displacing diene from rhodium in the course of reaction. The second method is preferred for preparation scale reactions since superior yields and catalysts lifetimes occur. The first method is rapid and is preferred for screening the effectiveness of different bisphosphine ligands in asymmetric induction, although chemical yields are poor.
Those diphosphines which are readily available were examined for their ability to induce chirality in the reduction of the substrate of interest. The ligand called R-Prophos, originally developed by Bosnich, Fryzuk, M. D.; Bosnich, B.; J. Am. Chem. Soc., 1979, 101, 3043; Fryzuk, M. D.; Bosnich, B.; J. Am. Chem. Soc.. 1977, 99, 6262, the disclosures of which are incorporated herein by reference, was found to be adequate for the preparation of L-BPA described below.
The use of cationic rhodium diphosphine complexes in catalytic hydrogenations is well established, but this is the first example in which a boronic acid group has been present on the olefin, and I have shown that it is well tolerated by the catalyst. The methodology described is adaptable to the synthesis of other .alpha.-amino acids containing this functionality. Moreover, the tolerance for this group suggests that other boron containing moieties, such as carboranes or closo-borane dianions could also be tolerated.
Another object of the invention is the method of making L-BPA comprising the steps of protecting 4-bromobenzaldehyde with ethylene glycol in the form of 4-bromobenzaldehyde ethylene glycol acetal, sequentially reacting 4-bromobenzaldehyde ethylene glycol acetal with Mg to produce the Grignard reagent and thereafter reacting with tributyl borate and then converting to an aqueous acid environment to form 4-boronobenzaldehyde, reacting 4-boronobenzaldehyde with diethanolamine to form 4-boronobenzaldehyde diethanolamine ester, condensing the 4-boronobenzaldehyde diethanolamine ester with 2-phenyl-2-oxazolin-5-one to form an azlactone, reacting the azlactone with an aqueous alkali metal hydroxide to form z-.alpha.-benzoylamino-4-boronocinnamic acid, asymmetrically hydrogenating the z-.alpha.-benzoylamino-4-boronocinnamic acid in the presence of a chiral diphosphine catalyst selected from the group including (consisting of) R-Prophos, Dipamp, Norphos, [(R)-1,2-bis (diphenylphosphinopropane)]rhodium(I) tetraflouroborate to form L-(+)-N-benzoyl-4-boronophenylalanine, and thereafter acidifying the L-(+)-N-benzoyl-4-boronophenylalanine in an organic medium to produce L-BPA.
Still another object of the invention is a method of making L-BPA comprising the steps of forming an ester of 4-boronobenzaldehyde, condensing the 4-boronobenzaldehyde ester with 2-phenyl-2-oxazolin-5-one to form an azlactone, reacting the azlactone with an alkali metal hydroxide to form z-.alpha.-benzoylamino-4-boronocinnamic acid, L asymmetrically hydrogenating the z-.alpha.-benzoylamino-4-boronocinnamic acid in the presence of a chiral diphosphine catalyst selected from the group including (consisting of) [(R)-1,2-bis (diphenylphosphinopropane)]rhodium(I) tetraflouroborate to form L-(+)-N-benzoyl-4-boronophenylalanine, and thereafter acidifying the L-(+)-N-benzoyl-4-boronophenylalanine in an organic medium to produce L-BPA.
A final object of the invention is a method of making L-BPA comprising the steps of asymmetrically hydrogenating z-.alpha.-benzoylamino-4-boronocinnamic acid in the presence of a chiral diphosphine catalyst selected from the group including (consisting of) R-Prophos, Dipamp, Norphos, [(R)-1,2-bis (diphenylphosphinopropane)]rhodium(I) tetraflouroborate to form L-(+)-N-benzoyl-4-boronophenylalanine, and thereafter acidifying the L-(+)-N-benzoyl-4-boronophenylalanine in an organic medium to produce L-BPA.
The invention consists of certain novel features and a combination of parts hereinafter fully described, illustrated in the accompanying drawings, and particularly pointed out in the appended claims, it being understood that various changes in the details may be made without departing from the spirit, or sacrificing any of the advantages of the present invention.